Amanda S. de Miranda

Lipases: Valuable catalysts for dynamic kinetic resolutions

Dynamic kinetic resolutions have proven to be a useful method for the preparation of enantiopure compounds from racemates, leading to the formation of a single enantiomer in theoretically 100% yield. Because lipases are ubiquitous, versatile, stereoselective and robust biocatalysts, they have been successfully applied as co-catalysts in these reactions, being mostly combined with metals in the chemoenzymatic dynamic kinetic resolutions of alcohols and amines.

Ethyl acetate as an acyl donor in the continuous flow kinetic resolution of (±)-1-phenylethylamine catalyzed by lipases

The synthesis of chiral amines is still a challenge for organic synthesis since optically pure amines are of great importance for the pharmaceutical and agrochemical industries. Among all the methodologies developed until now, chemoenzymatic dynamic kinetic resolution has proven to be useful for the preparation of enantioenriched primary chiral amines. In our continuous efforts toward the development of a continuous flow process, herein we report our results on the continuous flow kinetic resolution of (±)-1-phenylethylamine leading to the desired products with high enantiomeric ratios (>200) and short residence times (40 minutes) using ethyl acetate as the acyl donor.

Chiral Chlorohydrins from the Biocatalyzed Reduction of Chloroketones: Chiral Building Blocks for Antiretroviral Drugs

E. coli cells that contain overexpressed alcohol dehydrogenases (ADHs) were screened as biocatalysts for the stereoselective reduction of chloroketones 5 a–d, the corresponding halohydrins 6 a–d of which are building blocks in the synthesis of antiretroviral drugs. Among them, ADH from Sphingobium yanoikuyae was found to reduce chloroketone 5 c with a high stereoselectivity (90 % de) and conversion (85 %) to furnish threo halohydrin (R,S)‐6 c. ADH from Ralstonia sp. (RasADH) was able to reduce 5 a and 5 b with complementary diastereoselectivity to provide access to both threo and erythro halohydrins through “substrate‐based” stereocontrol. The RasADH‐catalyzed reductions were optimized to provide (R,S)‐6 a with 98 % conversion and 84 % diastereomeric excess (de) and (S,S)‐6 b with 95 % conversion and 86 % de. Molecular modeling studies showed that 5 b, which features a carboxybenzyl protecting group, is able to bind to the enzyme catalytic site in an “inverted” mode in comparison to tert‐butyloxycarbonyl‐ and methyloxycarbonyl‐protected substrates 5 a and 5 c, which sheds light on the observed switching of the stereopreference. RasADH‐catalyzed reductions were optimized to provide (R,S)‐6 a with 98 % conversion and 84 % de and (S,S)‐6 b with 95 % conversion and 86 % de.

Ammonium formate as a green hydrogen source for clean semi-continuous enzymatic dynamic kinetic resolution of (+/−)-α-methylbenzylamine

The chemoenzymatic dynamic kinetic resolution of (+/−)-α-methylbenzylamine under continuous flow conditions in the presence of Pd/BaSO4 as racemization catalyst and ammonium formate as reductant is described. Under the conditions good conversions and excellent enantiomeric excess are reported.

Continuous flow dynamic kinetic resolution of rac-1-phenylethanol using a single packed-bed containing immobilized CAL-B lipase and VOSO4 as racemization catalysts

Herein, we report a method for the continuous flow DKR of rac-1-phenylethanol catalyzed by CAL-B and VOSO4, using a single packed-bed containing both catalysts. Taking advantage of continuous flow techniques to circumvent compatibility issues, the DKR of rac-1-phenylethanol could be performed continuously to give enantiopure (R)-esters with excellent conversions and high productivities.